ardiac effects of relaxin

TiPS -june
7993 [Vol. 141
231
same response may be applied to
G protein-linked receptors, particularly those without introns. It is
postulated that many of the genes
encoding the G protein-linked
receptor family evolved from a
single precursor gene (possibly an
opsin gene) that lost its introns
approximately
1 billion
years
agoz3. Since then, gene duplication events have resulted in
many related genes. These intronless genes are so small that they
are more likely to be functional,
when
duplicated,
than
large
intron-containing genes and have,
therefore, diverged into a large,
related family of functional receptors. These events would, therefore, allow an increase in the
diversity of receptors available
and correspondingly in the level
of complexity possible, particularly in the brain, conferring an
evolutionary advantage. So, why
have G protein-linked 5-HTI-like
receptors diversified
so extensively? Answer: because they can!
MARGARET
S. BEER,
DEREK N. MIDDLEMISS
AND
GEORGE MCALLISTER
Merck Sharp
and Dohme
Lnboratories,
Neuroscience Research Centre, Terlings Park,
Eastwick
Road,
Harrow,
Essex,
UK
CM20 2QR.
References
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R. L. (1992) Trends Pharmaco/. SC;. 13, 152-159
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N. S. and Middlemiss,
D. N.
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L. M. and Middlemiss, D. N. (1993) Eur.
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(in press)
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University Science Books, pp. 37-47
Is the relaxin system a target for drug development?
ardiac effects of relaxin
In a recent issue of TiPS, Kakouris
and colleagues’
reported that
human relaxin gene 2 product
causes
concentration-dependent
positive chronotropic and inotropic effects by acting directly on
specific receptors in the rat isolated atria. On the basis of these
findings,
together
with
the
demonstration of specific highaffinity binding sites for relaxin in
the rat heart2 as well as of the
increase in serum relaxin concentrations during the first trimester
of human pregnancy3, Kakouris
and colleagues’ imply that relaxin
may be responsible for the elevation of cardiac output during
pregnancy.
The
authors
also
suggest’ that ‘the relaxin system
(receptors, degradation mechanisms, cell signalling, etc.) could be
a novel target for the development
of potential inotropic agents’.
We believe that these assertions
are, to say the least, premature, for
several reasons. First, the highly
preferential venodilator effect of
relaxin
to decreased
leading
venous blood velocity* will tend to
reduce circulating blood volume,
venous return and, consequently,
cardiac output. Secondly, the ensuing tachycardia with relaxin
might partly offset the potential
cardiotonic
advantage
of its
action. Thirdly, it should be noted
that while ‘the binding of 32P
relaxin . . . was seen clearly in the
heart atria, . . . the ventricles did
not show detectable binding” (see
also Fig. 1 in Ref. 2). Indeed, our
recent observations dealing with
the cardiac effects of 5-HT have
0
established that the increase in
contractility
induced
by this
amine in the atrium of both pigs5,‘j
and humans7 is not observed in
the ventricular myocardium.
We therefore
suggest
that,
although
relaxin
elevate
may
czdiac output by increasing heart
rate, it is unlikely
that relaxin
would do so via a positive inotropic effect on the ventricular
myocardium.
This signifies
that
the approach of developing potential inotropic
agents
via the
relaxin system will probably not
be very rewarding.
References
1 Kakouris,
H., Eddie,
L. W. and
Summers, R. J. (1993) Trends Dharmacol.
sci. 14, 4-6
2 Osheroff,
P. L., Cronin,
M. J. and
Lofgren, J. A. (1992) Pror. Nat/ Acod. S.i
USA 89,2384-2388
3 Bell. R. 1. et nl. (1987) Obstet. Gvnfcol. 69,
58i58<
4 Bigazzi, M., Del Mese, A., Petrussi, F.,
Casali. R. and Novelli, G. I’. (1986) Actn
Endoc;inol. 112, 296-249
5 Saxena,
I’. R., Villalirn,
C. M.,
Dhasmana,
K. M. and Verdouw, I’. D.
(1992) Naunyn-Schnlied. Arch. Pharnmcof.
346, 629-636
6 Schoemaker, R. G., Du, X. Y., Bax, W. A.
and Saxena,
P. R. (1992) Naunyr~S&tried. Arch. Phnrmacof. 346, 486-489
7 Schoemaker, R. G., Du, X. Y., Bax, W. A.
and Saxena, I’. R. (1993) Eur. 1. Phnrmncof. 239, 103-105
PRAMOD R. SAXENA,
WILLEM
A. BAX, XIAO Y. DU AND
REGIEN G. SCHOEMAKER
Depnrltneut o/ Phnrmncology and Cardiounscrrlar Resenrch Olstitrrfe ‘COEUR’,
Factrlty
of Mcdicitle and Hcnlfh
Sriences. Ernsnrus
University Rottcrdnwl, PB 1738, 3000 DR
Rotterdarn, The Nelherlnnds.
1993, Elscvicr Scirnce Puhhshrrs Ltd (UK)
0165 - hl47/93/BOh.O0

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